Microbiota restricts trafficking of bacteria to mesenteric lymph nodes by CX3CR1hi cells

Abstract

The intestinal microbiota have critical roles in immune system and metabolic homeostasis, but they must be tolerated by the host to avoid inflammatory responses that can damage the epithelial barrier separating the host from the luminal contents1-6. Breakdown of this regulation and the resulting inappropriate immune response to commensals are thought to lead to the development of inflammatory bowel diseases (IBDs) such as Crohn's disease and ulcerative colitis7. We hypothesized that the intestinal immune system is instructed by the microbiota to limit responses to luminal antigens. We demonstrate that, at steady state, the microbiota inhibit the transport of both commensal and pathogenic bacteria from the lumen to a key immune inductive site, the mesenteric lymph node (MLN). However, in the absence of Myd88 or under conditions of antibiotic-induced dysbiosis, non-invasive bacteria trafficked to the MLN in a CCR7-dependent manner and induced both T cell responses and IgA production. Trafficking was carried out by CX3CR1hi mononuclear phagocytes, an intestinal cell population previously reported to be non-migratory8. These findings define a central role for commensals in regulating the migration to the MLN of CX3CR1hi mononuclear phagocytes endowed with the ability to capture luminal bacteria, thereby compartmentalizing the intestinal immune response to avoid inflammation.

Differentiation of CD11c + CX 3 CR1 + cells in the small intestine requires Notch signaling

“…Epithelial cell recognition of such microorganisms is required for the maintenance of immune homeostasis in the gut (4,28). CD11c + CX 3 CR1 + cells contribute to the sampling of intestinal antigens (7-9), and they are crucial for the trafficking of bacteria to lymph nodes under dysbiotic condition (10 CD11c-Cre-mediated deletion of Notch1 or Notch2 disturbs the differentiation of CD11c + CX 3 CR1 + cells. The Notch3-deficient population was normal in size, although Notch3 was highly expressed on the R3 population.…”

“…The CX3C chemokine receptor 1 (CX 3 CR1) + cells that express integrin αX (CD11c) and a macrophage marker, F4/80 but not CD103 are crucial for the sampling of luminal antigens through their use of projecting dendrites that penetrate the epithelial cell layer (7)(8)(9). Furthermore, CD11c + CX 3 CR1 + cells are involved in the trafficking of commensal bacteria into mesenteric lymph nodes in the absence of Myd88 or under dysbiotic conditions (10) and transfer the luminal soluble antigen to integrin αM (CD11b) + CD103 + DCs via the gap junction to induce oral tolerance (11). The exact molecular mechanism that controls the development or differentiation of CD11c + CX 3 CR1 + cells remains unclear.…”

Endoscopic photoconversion reveals unexpectedly broad leukocyte trafficking to and from the gut

“…It was recently shown that, at steady state, the intestinal microbiota controls transport of both pathogenic and commensal bacterial antigens from the gut lumen to the MLNs, which relies on ferrying by mononuclear phagocytes (9). More generally, most investigators adhere to the concept that both cells and antigens drain from the gut directly into the MLNs.…”

Natural Childbirth and Breastfeeding as Preventive Measures of Immune- Microbiome Dysbiosis and Misregulated Inflammation

“…This balance appears to be crucial in regulating subsequent immune responses and avoiding inflammation-driven disease. Recently, Dielh et al [59] demonstrated in a mouse model that steady-state commensal bacteria help to compartmentalize immune stimulation by restricting the transport of commensal and pathogenic bacteria in the gut to the mesenteric lymph nodes (sites of immune response stimulation). This homeostatic regulation limits the likelihood of misregulated inflammation, which could promote chronic diseases such as inflammatory bowel disease (IBD).…”